Hydroxyalkyl substituted azetidinone derivatives, such as ezetimibe ([1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)azetidin-2-one]) represented by formula XII, are useful as hypochlesterolemic agents in the prevention and treatment of atherosclerosis.
Several processes have been reported for the preparation of diphenylazetidinones. (Journal of Organic Chemistry, 1999, 64, 3714, Journal of Medicinal Chemistry, 1998, 41, 973, U.S. Pat. Nos. 5,631,365; 5,886,171; 6,207,822; 6,133,001; 5,856,473, WO2005/066120, JP 2002-531546, JP 2005-53931).
These processes involve that the β-lactam ring construction using 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) (method 1) or asymmetric reduction of derivatives having a carbonyl group in a side chain at the 3-position of a (3-lactam ring such as (4S)-(benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (X) (method 2).
In Method 1, the intermediate, the hydroxyl group of 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) is protected with a suitable protecting group such as a trimethylsilyl or t-butyldimethylsilyl group, was used (U.S. Pat. No. 6,207,822, WO2005/066120, JP 2002-531546, JP2005-53931). 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) is synthesized by stereoselective microbial reduction of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) (U.S. Pat. No. 5,618,707).
It is reported that 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) is synthesized by asymmetric reduction of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) (U.S. Pat. Nos. 6,207,822; 6,627,757, Tetrahedron Letters, 2003, 44, 801.) These processes are a reduction by a borane-dimethylsulfide or borane-tetrahydrofuran complex using (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(1,2-c)(1,2,3)-oxazaborolidine [(R)-MeCBS; XIII] as a catalyst to afford the corresponding alcohol in high enantioselectivity.
However, the enatioselectivity of the reduction depends on the rate and mode of addition of the borane-complex, moisture sensitivity of the reaction medium and the reaction temperature. Moreover, the reduction using a chiral catalyst leads to problems associated with the formation of over-reduced products, such as compound (XIV) (Tetrahedron Letters, 2003, 44, 801).
Borane-dimethylsulfide and borane-tetrahydrofuran-complex are expensive and toxic. Furthermore, the handling of these reagents is not easy in large production due to borane being a gas. (R)-MeCBS (XIII) is commercially available, but it is expensive. Moreover, a recycle process is required since (R)-2-(diphenylhydroxymethyl)pyrrolidine (XV), the product that (R)-MeCBS (XIII) is decomposed to by workup operations, is recovered. In this case, it is necessary that an expensive boron carrier, such as trimethylboroxine, be prepared (R)-MeCBS (XIII).

WO2005/066120 discloses synthesis methods of 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) and (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester (IX) using (−)-B-chlorodiisopinocampheylborane (XVI) as a reducing agent.

(5S)-5-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester (IX) is converted to 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) in this patent. This reaction also shows a high selectivity, however, a stoichiometric amount of reducing agent is necessary.
In method 2, (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (XI) is produced in high stereoselectivity by borane-complex asymmetric reduction of (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (X) using (R)-MeCBS (XIII) as a catalyst. Compound (XI) is converted to ezetimibe (XII) by the removal of a benzyl group (Journal of Organic Chemistry, 1999, 64, 3714). However, this process also uses expensive (R)-MeCBS (XIII) and borane-complex.
The asymmetric reduction of aromatic ketones by sodium borohydride, chlorotrimethylsilane and a catalytic amount of optically active 2-diphenylhydroxymethyl)pyrrolidine (XV) system (Tetrahedron Letters, 2000, 41, 10281) has been reported. This reaction doesn't require a low reaction temperature. Furthermore, cheap and low toxic reagents are used in this reduction system. Moreover, 2-(diphenylhydroxymethyl)pyrrolidine (XV) is easily recovered during workup operations in a high yield, and recyclable after purification such as recrystallization. Reduction of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) by this system gives 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VIII) in a high yield and enantioselectivity [1 g scale ((R)-2-(diphenylhydroxymethyl)pyrrolidine 10 mol %): de 87%]. However, a tendency of decreased enantioselectivity of the product is observed at scale-up production (10 g scale ((R)-2-(diphenylhydroxymethyl)pyrrolidine 10 mol %): de 74%). Accordingly, the development of the catalyst, which shows a high enantioselectivity in large scale production, is desired.